title: Ubiquitination of K-Ras enhances activation and facilitates binding to select downstream effectors.
abstract: The guanosine triphosphate (GTP)--loaded form of the guanosine triphosphatase (GTPase) Ras initiates multiple signaling pathways by binding to various effectors, such as the kinase Raf and phosphatidylinositol 3-kinase (PI3K). Ras activity is increased by guanine nucleotide exchange factors that stimulate guanosine diphosphate release and GTP loading and is inhibited by GTPase-activating proteins that stimulate GTP hydrolysis. KRAS is the most frequently mutated RAS gene in cancer. Here, we report that monoubiquitination of lysine-147 in the guanine nucleotide-binding motif of wild-type K-Ras could lead to enhanced GTP loading. Furthermore, ubiquitination increased the binding of the oncogenic Gly12Val mutant of K-Ras to the downstream effectors PI3K and Raf. Thus, monoubiquitination could enhance GTP loading on K-Ras and increase its affinity for specific downstream effectors, providing a previously unidentified mechanism for Ras activation.
authors.affiliation: 1Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Atsuo T
authors.initials: AT
authors.lastname: Sasaki
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Carracedo
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Anastasiou
authors.forename: Koh
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Emily Rose
authors.initials: ER
authors.lastname: Kahoud
authors.forename: Sasson
authors.initials: S
authors.lastname: Haviv
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D002846:Chromatography, Affinity; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D053719:Tandem Mass Spectrometry; D054875:Ubiquitination / Q000502:physiology*; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D006160:Guanosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D048490:raf Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D008239:Lysine